Targeting autophagy in cancer management - strategies and developments

Abstract

Autophagy is a highly regulated catabolic process involving lysosomal degradation of intracellular components, damaged organelles, misfolded proteins, and toxic aggregates, reducing oxidative stress and protecting cells from damage. The process is also induced in response to various conditions, including nutrient deprivation, metabolic stress, hypoxia, anticancer therapeutics, and radiation therapy to adapt cellular conditions for survival. Autophagy can function as a tumor suppressor mechanism in normal cells and dysregulation of this process (ie, monoallelic Beclin-1 deletion) may lead to malignant transformation and carcinogenesis. In tumors, autophagy is thought to promote tumor growth and progression by helping cells to adapt and survive in metabolically-challenged and harsh tumor microenvironments (ie, hypoxia and acidity). Recent in vitro and in vivo studies in preclinical models suggested that modulation of autophagy can be used as a therapeutic modality to enhance the efficacy of conventional therapies, including chemo and radiation therapy. Currently, more than 30 clinical trials are investigating the effects of autophagy inhibition in combination with cytotoxic chemotherapies and targeted agents in various cancers. In this review, we will discuss the role, molecular mechanism, and regulation of autophagy, while targeting this process as a novel therapeutic modality, in various cancers.

Keywords: autophagy inhibition; chemotherapy; tumor microenvironment.

Figure 1

Regulation of autophagy. Notes: mTOR is one of the most important regulators of autophagy. mTOR and other pathways including cAMP, LKB, AMPK, and PKA merge at mTORC1. AMPK inhibits mTORC1 by direct interaction or by indirect activation of the TSC2 protein. The mTORC1 substrate p70S6K is a positive regulator of autophagy. Another important upstream factor is AKT/PKB, which acts a negative regulator of the TSC1/2 complex. In addition to energy depletion and hypoxia, the RAS, RAF, MEK, and ERK pathway is also involved in regulation of autophagy. The autophagic processes require induction, phagophore assembly (nucleation), sequestration, autophagosome formation, and autophagolysosome formation. The initial phase involves the initiation of the ULK complex, including ULK1/2, Atg13, Atg101, and FIP200. The activation of the PtdIns3K complex (Beclin-1, Vps34, and Vps 15), Vps, is an essential step in phagophore assembly (membrane nucleation). The E1-like enzyme Atg7 activates Atg12 and LC3-I, and the E2-like enzymes Atg10 (for activation of Atg12) and Atg3 (for LC3-I). Atg5 is conjugated to the Atg12 protein and this complex acts as an E3 ubiquitin ligase to catalyse the conjugation of LC3-I to PE in the process of sequestration. The subsequent autophagosome formation is dependent on the Atg12–Atg5–Atg16 complex. Once autophagosome formation is completed, the Atg12–Atg5–Atg16 complex dissociates from autophagosomes to allow Atg4 access to LC3-II for deconjugation from the lipid PE. Later, the lysosome merges with the autophagosome to form an autolysosome, which degrades the cytosolic macromolecules, proteins, and organelles. Depending on the cellular status, stress signal, and duration, the process leads to either cell death or cell survival. Abbreviations: AKT/PKB, protein kinase B; mTOR, mammalian target of rapamycin; TAK, thylakoid membrane protein kinase; LKB, liver kinase B; AMPK, adenosine monophosphate kinase; PKA, protein kinase A; TOR, target of rapamycin; LC3, microtubule-associated protein 1 light chain; PE, phosphatidylcholine; cAMP, cyclic adenosine monophosphate.